1. Field of the Invention
The present invention relates to novel cephalosporin derivatives, processes for their preparation and antibacterial agents containing them as active ingredients. The present invention also relates to novel isoquinoline derivatives which are intermediates of said cephalosporin derivatives and a process for their preparation.
2. Description of the Prior Art
A number of cephalosporin compounds have been synthesized which have a 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamido group as a side chain at the 7-position of the cephem nucleus. As publications which disclose such compounds, Japanese Unexamined Patent Publication Nos. 102293/1977, 116492/1977, 137988/1978, 9296/1979, 154786/1979, 157596/1979, 154980/1980, 6187/1981, 59895/1982, 99592/1982, 92394/1982 and 174387/1983, may be mentioned. It is suggested that such compounds exhibit activities against Gram-positive bacteria and cephalosporin resistant Gram-negative bacteria including Pseudomonas aeruginosa, and they have excellent antibacterial activities and a broad antibacterial spectrum. However, few of them are substantially active against glucose non-fermentative Gram-negative rods, such as Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia and Acinetobacter calcoaceticus.
Further, Japanese Unexamined Patent Publication Nos. 57386/1983 and 130294/1989 disclose compounds having an isoquinoliniomethyl group at the 3-position of the cephem nucleus. Japanese Unexamined Patent Publication No. 57386/1983 discloses unsubstituted and mono-substituted isoquinoliniomethyl groups. A number of substituents are mentioned. However, so long as a hydroxyl group is concerned, only a 5-OH derivative and a 8-OH derivative have been synthesized. Japanese Unexamined Patent Publication No. 130294/1984 discloses that the isoquinoline nucleus may have a number of substituents. However, only the 5-OH derivative has been practically synthesized. With respect to the hydroxyl group-substituted compounds, these prior art references give merely general statements, and no data on the antibacterial activities are given. Further, there is no disclosure which teaches that the isoquinoline ring may have two hydroxyl groups, and there is no suggestion at all about 6,7-dihydroxy derivatives having adjacent hydroxyl groups.
Since .beta.-lactam antibiotics exhibit selective toxicity only against bacteria and present no substantial effects against animal cells, they have been widely used as antibiotics having no substantial side effects for the treatment of infectious diseases caused by bacteria, and thus they are highly useful drugs.
However, in recent years, glucose non-fermentative Gram-negative rods, particularly Pseudomonas aeruginosa have been frequently isolated as causative organisms of refractory infections from immuno-compromised patients, which has posed a serious problem. Therefore, it is desired and beneficial as well to provide antimicrobial agents with improved activity against such bacteria.
Further, as the starting compound of the formula VIII given hereinafter, there may be mentioned 6,7-dibenzyloxyisoquinoline and 6,7-dimethoxyisoquinoline. A process for preparing 6,7-dimethoxyisoquinoline is disclosed in Journal of the American Chemical Society, Vol. 79, p 3773 (1957), and J. Chem. Soc. Perkin Trans. I, p 2185 (1974) and p 2190 (1974). However, the isoquinoline derivatives of the formula III and VII given hereinafter, which are the intermediates of the cephalosporin derivatives of the present invention, are new compounds not disclosed in any literature.